Heart failure is often defined as the inability of the heart to deliver a supply of oxygenated blood sufficient to meet the metabolic needs of peripheral tissues, both at rest and during exercise. See generally, Hurter, Jr., “Congestive Heart Failure”, in Scientific American: Medicine, Volume 1 (I:II), eds. Dale and Federman (Scientific American, Inc. 1994). Heart failure is a common outcome of hypertension or post-myocardial infarction and is a major contributor to cardiovascular morbidity and mortality. The clinical presentation of heart failure is an energy deprived heart, with altered calcium ion homeostasis, energy metabolism, and decreased contractile reserve (see e.g. Ingwall, Circulation 87 (Suppl VII):58-62 (1993)).
Hypertrophy develops in response to chronic overloading of the heart, such as occurs in systematic hypertension or aortic stenosis. Hypertrophy entails an increase both in size of the individual muscle cells and in the overall muscle mass. While cardiac hypertrophy is thought to be an initial compensatory response to increased hemodynamic load, restoring lost function and normalizing wall stress, hypertrophy is also an independent risk factor for progression to decompensated heart failure (Kannel, in Congestive Heart Failure W. K T, Ed. (WB Saunders Co, 1989) pp. 1-9; A. M. Feldman, JAMA 267:1956-61 (1992); Katz, TCM 5:37-44 (1995); Konstam, et al., Circulation 86:431-438 (1992); Shubeita, et al., J. Biol. Chem. 265:2055-20562 (1990)). Clinical trials in heart failure with angiotensin converting enzyme inhibitors suggest that part of the benefit of these inhibitors derives from attenuation of cardiac hypertrophy, structural remodeling and fibrosis (Chien et al., FASEB J. 5:3037-3046 (1991); Boheler et al., TCM 2:176-182 (1992)).
Experiments in animal model systems and cell culture have demonstrated that cardiac hypertrophy is associated with changes in gene expression (Izumo et al., Proc. Natl. Acad. Sci. USA 85:339-343 (1988); Calderone et al., Circulation 92: 2385-2390 (1995); Boluyt, et al., Circ. Res. 75:23-32 (1994); Feldman et al., Circ. Res. 73:184-192 (1993); Buttrick et al., J. Mol. Cell. Cardiol. 26:61-67 (1994)). The specific pattern of expression differences in vivo, referred to as the molecular phenotype, is dependent on the nature of the hypertrophic stimulus, as well as the stage of compensatory hypertrophy or decompensated failure (Knowlton, et al., J. Biol. Chem. 266:7759-7768 (1991); Shubeita, et al., J. Biol. Chem. 265:20555-20562 (1990); Pennica, et al., Proc. Natl. Acad. Sci. USA 92:1142-1146 (1995); Lai, et al., Am. J. Physiol. 271:H2197-H2208 (1996); Eppenberger et al., TCM 4:187-193 (1994); Ito et al., J. Clin. Invest. 92:398-403 (1993)). Studies with cultured cardiomyocytes and non-myocytes have also suggested a role for specific mediators in the response to increased hemodynamic load including adrenergic stimulation, gp130 signaling, endothelin-I, angiotensin II, and prostaglandin F2á, each with a distinct expressional and phenotypic response (Anversa et al., J. Mol. Cell. Cardiol. 12:781-795 (1980)).
Pressure overload leads to myocardial hypertrophy and the remodeling of muscular and collagenous compartments of the myocardium where the accumulation of fibrillar collagen is known to impair myocardial stiffness. Pressure overload can be achieved via surgical constriction of the aorta, aortic incompetence and aortocaval fistula (Mercadier et al., Circ. Res. 49:525-532 1981)). After abdominal aortic banding, left ventricular weight rises early and reaches a plateau by day 3 (Lindy et al., Circ. Res. 20:205-209 (1972); Turto, Cardiovasc. Res. 11:358-366 (1977)). Fibroblast proliferation also occurs with pressure overload, starting at day 2 and declining at day 7 after abdominal aortic banding (Morkin et al., Am. J. Physiol. 215:1409-1413 (1968)). Pressure overload caused cardiac hypertrophy is also associated with changes in gene expression (Lompre et al., Int. Cell Rev. 124:137-186(1990); Schwartz et al., Heart Failure 4:154-163 (1988)). For instance, cardiac hypertrophy secondary to pressure overload is accompanied by induction of two contractile protein isogenes, β-myosin heavy chain and á-skeletal actin (Swynghedauw, Phydiol. Rev. 66:710-749 (1986)).
Current clinical and preclinical work suggests that cardiac hypertrophy and heart failure are problems of cardiac growth and morphogenesis. A comprehensive understanding of the molecular phenotype in compensatory and pathological hypertrophy may thus be important to developing novel therapeutic strategies as well as understanding current treatments. However, the technical limitations of the candidate gene paradigm, in which specific genes of interest have been tested one or several at a time for their association with heart disease, mean that relatively little information is available compared to the entire complement of genes expressed in the to myocardium.
To obtain a more detailed understanding of the changes in gene expression occurring during pressure overload hypertrophy, the present inventors have used quantitative expression analysis (QEA) to identify expression differences in a rat surgical model of pressure overload (POL) induced cardiac hypertrophy. Abdominal aortic constriction leads to moderate hemodynamic overload (Boheler and Schwartz, TCM 2:176-182 (1992); Grossman e al., J. Clin. Invest. 56:56-64 (1975)), with the heart responding by concentric hypertrophy of the left ventricle, a process that leads to normalization of systolic wall stress (Morgan and Baker, Circulation 83:13-25 (1991)). Although increased load is thought to be the primary stimulus for this response, focal necrosis in the myocardium may also contribute to increased wall stress in this model.
This in vivo model is attractive for expression analysis as there are limited changes in tissue cellularity by infiltration of non-resident cells. The tissue reaction to acute POL is primarily due to an intrinsic response of the myocardium including hypertrophy of the cardiomyocytes, in addition to hyperplasia of endothelial, smooth muscle, and mesenchymal cells (Weber and Brilla, Circulation 83:1849-1865 (1991); Cooper, IV, Ann. Rev. Physiol. 49:501-518 (1987)). While this process is initially adaptive, there is ultimately a deterioration of contractile function accompanied by interstitial and perivascular fibrosis and increased wall stiffness (Kimura et al., Heart Circ. Physiol. 25:H1006-H1011 (1989); Batra and Rakusan, J. Cardiovasc. Pharmacol. 17 (Suppl 2):S151-S153 (1991)).